FR2493312A1 - 2-HYDROXY-5-PHENYLAZOBENZOIC ACID DERIVATIVES, PREPARATION METHOD AND THERAPEUTIC APPLICATIONS THEREOF - Google Patents

Abstract

THE INVENTION CONCERNS DERIVATIVES OF 2-HYDROXY-5-PHENYLAZOBENZOIC ACID OF GENERAL FORMULA: (CF DRAWING IN BOPI) IN WHICH X IS A -SO- OR -CO- AND R GROUP IS EITHER A NON-HETEROCYCLIC AROMATIC CORE. SUBSTITUTES OR SUBSTITUTES, EITHER A RADICAL OF GENERAL FORMULA - (CH) -Y, IN WHICH Y IS A HYDROXYL GROUP, A NON-SUBSTITUTE OR SUBSTITUTE AMINO GROUP, OR A CARBOXYL OR SULPHONIC ACID GROUP, AND N IS AN ENTIRE NUMBER OF CHOIS 1 AND 6, AND IN WHICH ONE OR MORE ATOMS OF HYDROGEN OF RADICAL ALCENE MAY BE REPLACED BY NON-SUBSTITUTED OR SUBSTITUTED AMINO GROUPS OR BY ALCOHYL RADICALS, AND IN WHICH THE RADICAL - (CH) -Y IS ATTACHED TO THE NITROGEN ATOM EITHER DIRECTLY OR THROUGH A BENZENE RING, PROVIDED THAT R IS DIFFERENT FROM RADICAL -CO-NH-CH-COOH; AND PHARMACEUTICALLY ACCEPTABLE ESTERS AND NON-TOXIC SALTS OF THESE COMPOUNDS. THE INVENTION ALSO CONCERNS A PHARMACEUTICAL COMPOSITION CONTAINING AT LEAST ONE OF THESE COMPOUNDS, THEIR PREPARATION PROCESS AND THEIR APPLICATIONS FOR THE TREATMENT OF ULCEROUS COLITIS.

Description

The present invention relates to novel pharmaceutical compositions

  containing derivatives, mostly new,

  2-hydroxy-5-phenylazobenzoic acid.

  Ulcerative colitis is a disease whose frequency increases

  and for which, so far, the only satisfactory treatment is the administration of salazosulfapyridine, the formulation of which is as follows COOH

NH - 502 - Q N = N "OH

  However, a serious disadvantage of salazosulfapyridine is to decompose in the intestinal tract, to give the

  sulfapyridine, which produces undesirable side effects

  ble. In addition, salazosulfapyridine is insoluble in water.

  We have just discovered that when the pyridyl

  famoyl of salazosulfapyridine is replaced by certain

  non-heterocyclic organic dyes, compounds are obtained that are very useful in the treatment of ulcerative colitis and have the great advantage that their decomposition in the pathway

  intestinal tract does not give rise to metabolic products

  desirable. In addition, many of them are soluble in water, which is interesting from the point of view of the facility

  administration, and possess very low acute toxicity.

  Thus, the present invention relates to compositions

  pharmaceutical compounds containing at least one compound of the general formula

the: COOH

R-NH-X N N "OH (I)

  wherein X is -SO2- or -CO-, and R is either an unsubstituted or substituted non-heterocyclic aromatic ring, preferably a benzene ring, or a radical of the general formula - (CH2) n -Y wherein Y is a hydroxyl group, an unsubstituted or substituted amino group, or a carboxylic acid or sulfonic acid group and n is an integer selected from 1 to 6, wherein at least one hydrogen atom of

  alkene radical may be replaced by non-amino groups

  substituted or substituted, or by alkyl radicals, and in

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  the radical - (CH2) rY is attached to the nitrogen atom either directly or via a benzene ring, and / or containing at least one non-toxic and pharmaceutically acceptable salt of said compound, supplemented with a diluent or a solid or liquid pharmaceutical carrier.

  Most of the compounds of the general formula (I) are new

  calves. Accordingly, the present invention also relates to novel compounds of the general formula wherein X is an SO 2 or -CO- group and R is a non-heterocyclic aromatic non-heterocyclic ring. substituted or substituted, preferably a benzene ring, is a radical of general formula - (CH2) n-Y5 wherein Y is a hydroxyl group or a carboxylic or sulfonic acid group and n is an integer selected from 1 to 6, in which one or more hydrogen atoms of the alkene radical may be replaced by unsubstituted or substituted amino groups, or by alkyl radicals, and wherein the radical - (CH2) nY is

  attached to the nitrogen atom either directly or through

  of a benzene ring, provided that R-NH-X- is dif-

  of the -CO-NH-CH 2 -COOH radical, and on the pharmaceutically acceptable esters and salts of these compounds, such as, for example, the alkali metal and alkaline earth metal salts, or

non-toxic amines.

  The amino-substituted groups present in the compounds of the present invention are preferably mono- or dialkylamino radicals, the alkyl parts of which contain up to 6, and preferably 3, carbon atoms; more specifically will be

  preferred is methyl or ethyl.

  The compounds of general formula (I) can be prepared by diazotising an amine of general formula

R-NH-X NH 2 (I)

  in which R and X have the same meanings as above; coupling is then carried out with salicylic acid; after which, if desired, the compound obtained is salified with an i

  non-toxic organic or inorganic base.

  The following examples are given as illustrations

of the present invention.

Example 1

  a) A mixture of 100 g of N-acetylsulfanilyl chloride, g of aniline sulphate and 80 g of sodium carbonate in 500 ml of acetone is heated for 5 hours under reflux, with stirring, cooled and then added to a mixture dilute hydrochloric acid and ice. The precipitate obtained was filtered, washed with water and with ethyl ether and then dried under vacuum at 50 ° C., giving 110 g.

  almost pure N-acetylsulfanilylanilide (melting point: 212-

215 C).

  b) 100 g of N-acetylsulfanilylanilide are heated for 3 hours under reflux in 150 ml of aqueous hydrochloric acid

  (volume ratio 1/1). After cooling, the reaction mixture

  is diluted with water and then cooled again to 00C.

  The 90 g of sulfanilylanilide hydrochloride that are deposited

  recovered by filtration, washed with iced water and recrystallized

  ethanol (melting point: 191-193.50C).

  (c) 10 g of sulfanilylanilide hydrochloride and 10 ml of

  concentrated hydrochloric acid in 600 ml of ethanol are gently heated until dissolved, then cooled to 50 ° C. and treated dropwise with 30 ml of a 10% aqueous solution of sodium nitrite. The reaction mixture is left standing for one hour at a temperature between 0 and 50C, then filtered. While maintaining a temperature between 0 and C, the filtrate is added dropwise to a solution of 5 g of salicylic acid in 100 ml of an aqueous solution containing 4 g of sodium carbonate and 7 g of sodium hydrate, cooled

  at 0C. The reaction mixture is allowed to stand for 3 hours.

  at room temperature for 20 hours, while maintaining

  pH above 8; after which, it is concentrated on a "rotavapeur" and acidified apparatus. The resulting viscous precipitate is separated and boiled with water several times to remove excess salicylic acid. The residue is dissolved in ethyl ether and the ethereal solution is washed with water, dried over anhydrous sodium sulfate and treated with charcoal. After having filtered and removed the ethyl ether, the crude product obtained is dissolved in a minimum volume of acetone and in ten times the volume of ethyl ether added to this mixture. After

  cooling, 3.5 g of 5- (4-phenylsulfamoyl)

  phenylazo) salicylic acid (mp 232-234 ° C).

  (d) 11 g of 5- (4-phenylsulfamoylphenylazo) -sa-

  licylic acid in 100 ml of ethanol with an ethanolic solution of an equivalent amount of sodium hydrate. The solution obtained is concentrated under a small volume at a temperature of C and under a pressure of 20 mmol / g; after which, a volume

  Equal of ethyl ether is added to the concentrate. Sodium 5- (4-

  phenylsulfamoylphenylazo) -salicylate is deposited after cooling.

  dissement; it is filtered, washed with ethyl ether and treated with

  petroleum ether (boiling point 40-60 ° C.) and dried under vacuum at 50 ° C. (mp 257 ° -259 ° C.). The yield is

12 g.

Example 2

  a) A solution of 22 g of 4-aminohippuric acid in 20 ml of hydrochloric acid and 200 ml of water is cooled to 0.degree. C. and treated dropwise, with stirring, with 80 ml of a solution. aqueous 10% sodium nitrite. The reaction mixture is stirred for 1 hour, after which a solution of 14 g of salicylic acid in 150 ml of a solution (normality: 2N) of sodium hydrate containing 15 g of carbonate is added dropwise. of sodium and cooled to 0 C. The reaction mixture is left overnight at room temperature, and is then poured into a mixture of ice and dilute hydrochloric acid. The fine precipitate obtained is extracted with boiling ethyl acetate and the solution is treated with charcoal. After filtration, the filtrate is evaporated to remove the solvent, then the residue is crystallized with boiling ethanol, giving 30 g of 5- (4-carboxymethylcarbamoylphenylazo) -salicylic acid (point

melting point 260 - 262 C).

  b) A solution of 11 g of 5- (4-carboxymethylcarbamoyl)

  phenylazo) -salicylic acid in 500 ml of hot ethanol is treated

  with an ethanolic solution containing two equivalents of hydra-

  and the deposit obtained is filtered, washed with ethanol and with ethyl ether, and dried under vacuum at 50 ° C. 12.5 g are obtained.

  disodium salt of 5- (4-carboxymethylcarbamoylphenylazo) -

  salicylic acid (melting point greater than 360 C).

Example 3

  9.71 g of amino hippuric acid are dissolved in a mixture of 40 ml of hydrochloric acid (2.5 N) and 10 ml of acid.

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  sulfuric acid (2.5 N), to which 50 g of ice are added. A solution of 3.5 g of sodium nitrite in 15 ml of water is added continuously at 0 ° C., the reaction mixture being well stirred during this operation. After 75 minutes at 0 ° C., the reaction mixture is added to a solution of 6.9 g of salicylic acid in 37 ml of a mixture of 9 parts by volume of a

  aqueous solution of sodium hydrate (5N) and firstly by volume

  of an aqueous solution of sodium carbonate (5N), the temperature

  by keeping ice at 0 C.

  After 15 minutes, 23 ml of a mixture of 4 parts by volume of hydrochloric acid (5N) and one part by volume of acetic acid are added slowly with stirring. The precipitate obtained is removed by filtration, washed with distilled water and dried under vacuum at 80 ° C., giving 17.2 g (100% of the theoretical value) of 5- (4-carboxymethylcarbamoylphenylazo) salicylic acid, which can be recrystallized with 80% acetic acid, aqueous acetone or aqueous dimethylformamide, giving a yellow crystalline product (minimum purity: 99%, yield: 80 to 95%)

melting point: 260-262 ° C).

Example 4

  a) 125 g of a fine powder of 4-nitrobenzoyl chloride are added, in small quantities and with stirring, to a solution of 70 g of alanine in 500 ml of water containing 65 g of sodium hydrate, and cooled to 5 ° C. The reaction mixture is stirred for 3 hours and then added to a mixture of ice and hydrochloric acid. The precipitate obtained is filtered, washed with water and then dried by suction. After crystallization of the dried product with hot acetone, 130 g of 4-nitrobenzoyl-e-alanine are obtained

(melting point: 164-165 ° C).

  b) 15 g of a fine powder of 4-nitrobenzoyl-e-alanine suspended in 200 ml of ethanol are stirred under a hydrogen atmosphere in the presence of 1 g of palladium on charcoal

  (5%), while gently lowering the temperature. When the

  Hydrogen sorption ceases, the reaction mixture is filtered and the filtrate concentrated to a small volume. By adding

  ethyl ether and on cooling, 4-amino-

  benzoyl-3-alanine. The yield is 11.5 g (melting point:

156 - 15 C).

  c) 8.8 g of 4-aminobenzoyl-β-alanine are triturated with 12 ml of hydrochloric acid and the paste obtained is dissolved in 100 ml

  of water. The solution is cooled to C - 5 C and added drop by drop.

  dropwise with stirring a solution of 3 g of sodium nitrite in ml of water cooled to 0 ° C. The diazotized solution is left standing for one hour at 0 ° C. and then added dropwise at 5 ° C. a solution made of 6 g of salicylic acid in 70 ml of water containing 3.6 g of sodium hydrate and 7 g of sodium carbonate. The pH of the final reaction mixture was adjusted to 8. It was stirred for 2 to 3 hours and then added to a mixture of dilute hydrochloric acid and ice. The precipitate obtained is removed by filtration, washed with water and dried by suction. Crystallization with hot ethanol gives 11.9 g of 5- (carboxyethylcarbamoyl-4-phenylazo) -salicylic acid (point

melting point: 254-255 ° C).

  10.7 g of the free acid are dissolved in 300 ml of hot ethanol and treated with a solution of 2.4 g of sodium hydrate in 25 ml of ethanol. The precipitate obtained is removed by filtration, washed with ethanol and with ethyl ether, and dried.

  under vacuum at 50 ° C., giving 11.5 g of the disodium salt of the acid 5-

  (carboxyethylcarbamoyl-4-phenylazo) -salicylic acid (melting point

greater than 350 C).

Example 5

  20 g of a fine nitrobenzoyl chloride powder are added in small quantities to 12.5 g of taurine in a solution made of 8 g of sodium hydrate and 50 ml of water. The mixture

  The reaction mixture is stirred for 3 hours and then acidified. Acid 4-

  precipitated nitrobenzoic acid is filtered and the filtrate distilled

  only at a pressure of 15 mm.Hg. The residue is extracted

  with boiling ethanol and the extract is then cooled, giving

  23.6 g of 4-nitrobenzoyltaurine (m.p.

280 C).

  (b) A solution made of 17 g of 4-nitrobenzoyltau-

  rinse in 100 ml of water under a hydrogen atmosphere in the presence of one gram of palladium on charcoal (5%) until hydrogen uptake ceases. The reaction mixture is

  then filtered; the filtrate is mixed with 20 ml of hydrochloric acid

  that and the suspension of hydrochloride obtained is cooled to -5 C.

  This product is added dropwise, with stirring, to a solution

  5 g of sodium nitrate in 30 ml of water. The diazo- solution

  The mixture thus obtained is stirred for 30 minutes and then added to 9.5 g of salicylic acid in a solution made of 11 g of sodium hydrate and 100 ml of water at a temperature of -2 ° C. the mixture for 3 hours, poured into a mixture of ice and 15 ml of hydrochloric acid, and then stirred for 30 minutes at a temperature of 0 C. The precipitate obtained is removed by filtration and washed with water. 'frozen water. Crystallization with 20% aqueous ethanol gives 18.2 g of - (sulfoethylcarbamoyl-4-phenylazo) -salicylic acid (melting point).

  greater than 350 C (decomposition)).

Example 6

  A solution made of 10 ml of ethanolamine in 120 ml of a

  10% aqueous solution of sodium hydrate is cooled to 5 C.

  30 g of a fine powder of 4-nitrobenzoyl chloride are added in small quantities. The reaction mixture is stirred

  for 24 hours and filtered. The resulting solid, which consists mainly of

  usually bis (4-nitrobenzoyl) ethanolamine, is hydrolyzed with 200 ml of aqueous ethanolic sodium hydrate to

  4% at room temperature for 24 hours. The reaction mixture

  The filtrate is added to the above filtrate, acidified and the 4-nitrobenzoic acid precipitate is removed by filtration. The filtrate is concentrated and 13 g of precipitated N-4-nitrobenzoyl ethanol amine are isolated. The mother liquor is distilled until dry and the residue boiled with ethanol. The concentration of the ethanolic extract gives an additional 5.3 g of the product

(melting point: 134-135 ° C).

  b) A solution of 21 g of N-4-nitrobenzoyl ethanolamine in 400 ml of ethanol is stirred under a hydrogen atmosphere in the presence of 1 g of palladium on charcoal (5%) until Hydrogen uptake ceases. The catalyst is filtered and the ethanolic solution is evaporated to dryness, giving a thick oil which slowly solidifies. Thin layer chromatography shows that the 4 aminobenzoylethanolamine thus obtained is more than 99% pure. It is used as it is

  for the next step of the synthesis.

  c) A solution made of 16 g of N-4- is cooled to -5 ° C.

  aminobenzoylethanolamine in 20 ml of hydrochloric acid and ml of water, which is then treated dropwise with stirring,

  with a solution of 7 g of sodium nitrate and 50 ml of water.

  The reaction mixture is stirred again for 1 hour and then added dropwise to 120 ml of a 10% aqueous solution of sodium hydroxide containing 13 g of salicylic acid, and

8 2493 12

  cooled to -2 C. The reaction mixture is stirred for 3 hours and the precipitate obtained is filtered, washed with ice water, dried by suction and crystallized with hot ethanol, giving 11 g of sodium 5- (4-hydroxyethylcarbamoylphenylazo) salicylate (melting point: 286-288 ° C (decomposition)). The filtrate, from which the sodium salt was removed, is acidified. The precipitate obtained is filtered, washed with water,

  dried by aspiration, carbonized in a mixture of ethyl acetate

  methanol (volume ratio: 2/1) and concentrated, giving 2.7 g.

  5- (4-hydroxyethylcarbamoylphenylazo) -salicylic acid, which is

  identical in all respects to the regenerated free acid of the sodium salt

  dium (melting point: 225-226 ° C (decomposition)).

Example 7

  a) 7 g of alanine in 65 ml of an aqueous sodium hydroxide solution are treated in small amounts, while

  stirring with 12.5 g of a fine powder of 4-nitrobenzene chloride

  zoyle. The reaction mixture is stirred for 20 hours, at 5 ° C., acidified, and the precipitate isolated, washed with water and dried by suction. A repeated fractional crystallization, by a mixture acetone - ethyl ether (ratio volume:

  2/1) gives 4-nitrobenzoylalanine (melting point: 199-

   C). b) 2 g of 4-nitrobenzoylalanine in 50 ml of ethanol are hydrogenated in the presence of 0.2 g of palladium on charcoal (5 t). After removing the catalyst and the solvent, a solid is obtained which is crystallized by an ethanol-ether mixture.

  ethyl (volume ratio 1/2), giving 4-aminobenzoylalazole

  nine (melting point: 198 - 199 C).

  c) a solution of 0.8 g of 4-aminobenzoyl chloride in 15 ml of hydrochloric acid (1N) is cooled to -5 C and diazotea

  with 5 ml of a 10% aqueous solution of sodium nitrate

  30 minutes. The reaction mixture is then added to a solution composed of 0.7 g of salicylic acid and 15 ml of water.

  containing 0.8 g of sodium hydrate and 0.5 g of sodium carbonate

  dium. After 2 hours, the reaction mixture is acidified and the precipitate obtained is isolated, dissolved in ethyl acetate and the solution is washed, dried and charred. The solution is then

  concentrated and cooled, giving 0.9 g of 5 - (: - methylcarbo)

  xymethylcarbamoyl-4-phenylazo) -salicylic acid (melting point:

252 - 254 C).

Example 8.

  a) Acetylsulfanilyl chloride is added in small quantities, at 5 ° C. and with stirring, to a solution made up of 15 g of 4-aminophenyl acetic acid and 10% aqueous sodium hydroxide solution. The reaction mixture is stirred for a further 4 hours and then added to a mixture of hydrochloric acid

  diluted and ice. The precipitate obtained is isolated, fixed by

  ethyl acetate, washed with water, dried and evaporated,

  giving 22 g of acetylsulfanilyl-4- (carboxymethyl) -anilide.

  b) 3.5 g of acetyl ether are heated under reflux for 2 hours.

  sulfanilyl-4- (carboxymethyl) -anilide in 7 ml of hydrochloric acid

  (5N), then the mixture is cooled, diluted in 20 ml of ice and water and cooled to -5 ° C. 8 ml of a 10% aqueous solution of sodium nitrite and after 30 minutes, the diazotized solution is added to 1.4 g of salicylic acid in 20 ml of an aqueous solution containing 2 g

  of sodium hydrate and 2 g of sodium carbonate at a temperature of

  The reaction mixture is stirred for 2 hours and then added to a mixture of hydrochloric acid and water. The precipitate obtained is isolated and dissolved in acetate

  of ethyl, and the solution is washed with water, dried and charred.

  By concentrating the filtered solution and adding an equal volume of ethyl ether, the desired product dissociates slowly

  crystals. 3 g of 5 - [(4-carboxymethylphenyl) -sul-

  4-famoyl-phenylazolsalicylic acid (mp 252-254 ° C).

Example 9.

  a) A solution of 12 g of 6-amino-hexanoic acid in

  ml of a 10% aqueous solution of sodium hydroxide is treated

  in small amounts with 9 g of a fine 4-nitrobenzoyl chloride powder. After 4 hours, the reaction mixture

  is added to a mixture of dilute hydrochloric acid and ice.

  The precipitate obtained is isolated, washed with water and crystallized by

  acetone, giving 12.6 g of (4-nitrobenzoyl) -6-aminohexa-

  no. (melting point: 148-150 ° C).

  (b) A solution of 6 g of (4-nitrobenzoyl) -6-aminohexa-

  in 150 ml of ethanol is hydrogenated in the presence of 0.5 g of palladium on charcoal (5%) until the reaction

  be perfect. The catalyst and the solvent are removed and the resi-

  is crystallized by an ethanol-ethyl ether mixture (

  port volume: 1/1), giving 4.7 g of (4-aminobenzoyl) -6-

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  aminohexanoic acid (m.p. 132 134 C).

  (c) A solution of 2.5 g of (4-aminobenzoyl) -6-amino-

  hexanoic acid in 15 ml of hydrochloric acid (2N) is cooled to -5 ° C. and treated dropwise, with stirring, with 8 ml of a 10% aqueous solution of sodium nitrite. The reaction mixture

  is stirred for 30 minutes, then added at a temperature of

  at -5 ° C., with salicylic acid in 20 ml of water containing 2 g of sodium hydrate and 1 g of sodium carbonate. After 3 hours, the reaction mixture is acidified and the precipitate

  obtained is isolated by centrifugation, dissolved in the acetate of

  thyl, washed, dried and concentrated in a small volume. After

  2.7 g of 5- (carboxypentylcarba-

  4-methylphenylazo) -salicylic acid (melting point: 238-239 ° C).

Example 10

  a) A solution of 13 g of copper sulphate in 60 ml of water, and a solution of 2 g of sodium hydrate in 30 ml

  of water are added simultaneously to a solution of 7.5 g of

  in 50 ml of water, adding followed by the addition of 50 ml of a 10% aqueous solution of sodium bicarbonate. Salt

  The precipitate is removed by filtration and the blue filtrate is added.

  with vigorous stirring to a solution of 7 g of 4-nitrobenzoyl chloride in 50 ml of acetone. The reaction mixture is stirred for 20 hours and the precipitate obtained is removed by filtration, washed with water, with methanol and with ethyl ether, and

  dried under vacuum at 50 ° C., giving the copper salt of the d- (4-

nitrobenzoyl) -lysine.

  (b) A suspension of 7 g of the copper salt of 6- (4-nitro-

  benzoyl) -lysine in 30 ml of water is stirred with 6 ml of hydrochloric acid until complete dissolution. Sulfuric acid is passed for 1 hour, then the cupric sulphide

  precipitate is removed by filtration. The filtrate is evaporated

  until the residue is taken up in 20 ml of hydrochloric acid.

  than and heated under reflux for 3 hours. The reaction mixture

  The cooled water is diluted in water, made alkaline by carbonate

  of sodium and extracted with ethyl acetate, giving 4.8 g of 6-

  (4-nitrobenzoyl) -lysine methyl ester, as a yellow oil. c) A solution of 1 g of methyl 6- (4-nitrobenzoyl) -lysine

  ester in 2 ml of methyl iodide and 0.2 ml of acetone is

  at rest for 20 hours at room temperature, after which NMR shows that the reaction is complete. Products

  volatiles are removed by evaporation, leaving 6- (4-nitro-

  benzoyl) -α, α-dimethyl-lysine methyl ester in the form of an oil.

  d) 1 g of 6- (4-nitrobenzoyl) -α, α-dimethyl-lysine methyl ester in 20 ml of ethanol is hydrogenated in the presence of 0.1 g of

  palladium on charcoal (5%) until the abolition of

  hydrogen sorption. The catalyst is removed by filtration and the filtrate evaporated to dryness. The residue is taken in 5 ml of hydrochloric acid (normality: 2N), cooled to -5 C and treated

  with 2.5 ml of a 10% sodium nitrite solution.

  After 30 minutes of resting, the clear solution is added at a temperature of -5 ° C., to a solution of 0.5 g of salicylic acid in 20 ml of an aqueous solution of sodium hydrate (1N). After a consecutive rest period of 3 hours at 20 ° C., the reaction mixture is acidified and extracted with ethyl ether to remove the unreacted salicylic acid. The aqueous phase is adjusted to a pH of 7 by adding an aqueous solution of sodium hydrate (1N) and the resulting solution is evaporated to dryness. The residue is further dried by the addition of toluene, followed by evaporation thereof, and the residue is extracted with methanol. The methanolic solution is concentrated

  under a small volume. After addition of ethyl ether and cooling

  the disodium salt of 5- (α-dimethylaminocarboxylic acid)

  pentylcarbamoyl-4-phenylazo) -salicylic acid precipitates out

  (melting point above 210 C (decomposition)).

Example 11

  a) A solution of 30 ml of N, N-diethylethylenediamine in ml of water is treated in small amounts, with stirring, with a fine powder of 4-nitrobenzoyl chloride. The reaction mixture is stirred for 20 hours and the precipitate obtained is removed by filtration, washed with water and with a solution

  aqueous solution of sodium carbonate, and crystallized by a mixture of

  ether oil and ether ether (volume ratio: 1/1) giving 6 g of N, N-diethyl- (4-nitrobenzoyl) -ethylenediamine

(melting point: 49-51C).

  b) A solution of 5 g of N, N-diethyl- (4-nitrobenzoyl) -

  ethylenediamine in 40 ml of ethanol is hydrogenated in the presence of 0.3 g of palladium on charcoal (5%), until

  the reaction is total. The catalyst and the solvent are removed

  and 5 g of N, N-diethyl- (4-aminobenzoyl) ethylene are obtained.

diamine in the form of an oil.

  c) A solution of 2.35 g of N, N-diethyl- (4-aminobenzoyl) -

  ethylenediamine in 20 ml of hydrochloric acid (2N) is cooled

  at -50 ° C. and treated with 8 ml of a 10% aqueous solution of sodium nitrite. The reaction mixture is stirred for 30 minutes and added to 1.4 g of salicylic acid in a solution of 1.6% sodium hydroxide and 2 g of sodium carbonate in ml of water. After 3 hours during which the temperature rose from 0 to 20 ° C, sodium chloride was added to the reaction mixture to liberate the desired diazo compound. This is then removed by filtration, washed with water and methanol

  dried, giving 2.3 g of 5- (diethylamino) ethylcarbamate

  4-methylphenylazo) -salicylic acid (melting point: 252-251 ° C (dec)). The pharmaceutical compositions according to the present invention

  contain at least one of the compounds (I), in admixture with a solid or liquid pharmaceutical carrier.

  Solid compositions for oral administration include tablets, pills, dispersible powders and granules. In these solid compositions, one of the compounds

  (I) is mixed with at least one inert diluent, such as

  calcium carbonate, starch, alginic acid or lactose. These compositions may also comprise, as is customary, additional substances, for example

  lubricants, such as magnesium stearate.

  Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs containing inert diluents, common to those skilled in the art, such as water

  and liquid paraffin. In addition to the inert diluents, these composi-

  may also include adjuvants, such as

  and suspending agents, sweeteners and agents

of palatability.

  The compositions according to the present invention for

  oral administration include capsules in the form of

  absorbable material, such as gelatin, containing at least one of the

* compounds (I), with or without the addition of diluents or excipients.

  The percentage of active product in the compositions of the present invention may vary; it is necessary, however, that it be in such a proportion that the dosage is

  suitable for the desired therapeutic effect. In general, the pre-

  The compositions of the present invention will be administered orally or parenterally to humans to provide between 500 and 5000 mg, and preferably between 500 and 2000 mg, of active ingredient per day.

  The following examples illustrate the pharmaceutical compositions

  in accordance with the present invention.

Example 12.

  600 mg of tablets are prepared which contain:

  disodium salt of 5- (carboxyethyl)

  carbamoyl-4-phenylazo) -salicylic acid 500 mg - starch 50 mg-lactose 45 mg magnesia stearate 5 mg Example 13 450 mg tablets are prepared which contain: - sodium 5- (4-carboxymethylcarbamoylphenyl azo) -salicylate 250 mg - starch 100 mg - lactose 95 mg - magnesium stearate 5 mg

  The tablets of Examples 12 and 13 are intended for use by

  administration to humans for the treatment of ulcerative colitis.

  An attempt has been made to establish an accurate profile of

  the oral toxicity of the disodium salts of 5- (4-carboxy-

  methylcarbamoylphenylazo) -salicylic acid and 5- (carboxymethyl)

  ethylcarbamoyl-4-phenylazo) -salicylic acid, using rats and mice as experimental animals, but this was not possible because of their low toxicity. No deaths were observed during the administration of the carboxymethyl compound to mice with a dosage of 3 g / kg, and to rats with a dosage of

  2 g / kg; likewise, no deaths were observed during the administration

  treatment of the carboxyethyl compound with mice, with a dosage of

  4 g / kg, and rats, with a dosage of 2 g / kg.

  We also conducted experiments on groups of 6

  male rats, "Wistar" breed, to verify that the new compounds

  of the present invention are divided in the same way as

  sulfasalazine, releasing 5-aminosalicylic acid (5-ASA).

  The compounds tested were administered at a rate of 45 to 50 mg / kg.

  The results obtained are given in the following table.

  tested compounds of the measured dose of 5-ASA feces total urine sulfasalazine 26 + 4 17 + 2 43 + 4 Example 1 24 + 3 19 + 3 43 + 3 Example 2 17 + 3 17 + 6 34 +5 Example 4 22 + 2 14 + 2 36 + 3 Example 5 26 + 3 15 + 2 41 + 5 Example 6 22 + 2 19 + 3 41 + 4

  The results above clearly demonstrate that the new

  compounds of the present invention disintegrate from the

  same way as sulfasalazine, and it can be expected to exert

  an effect at least as beneficial as sulfasalazine, but

  without the disadvantage of giving rise to other compounds exerting

  with undesirable side effects, such as sulfapyridine

  formed from sulfasalazine.

Claims (14)

  1. Derivatives of 2-hydroxy-5-phenylazobenzoic acid, of the general formula: COOH R -NH -X - NN OH   wherein X is -SO2- or -CO- and R is either an unsubstituted or substituted non-heterocyclic aromatic ring or a radical of the general formula - (CH2) n-Y, wherein Y   is either a hydroxyl group or a substituted amino group   titué or non-substituted, a carboxylic acid or sulfonic acid group, and n is an integer selected from 1 to 6, and wherein one or more hydrogen atoms of the radical   alkene may be replaced by substituted amino groups.   or unsubstituted or by alkyl radicals, and in which   the radical - (CH2) n -Y is attached to the nitrogen atom either directly   by means of a benzene ring, provided that   that R-NH-X- is not the radical -CO-NH-CH2-COOH,   and non-toxic esters and salts pharmacologically ceptables of said derivatives.   2. 5- (4-Phenylsulfamoylphenylazo) -salicylic acid and the sodium salt of it.   3. Sodium salt of 5- (4-carboxymethylcarbamoyl)   phenylazo) -salicylique. 4. 5- (carboxyethylcarbamoyl-4-phenylazo) salicylic acid and the sodium salt thereof.   5. 5- (Sulfoethylcarbamoyl-4-phenylazo) -salicylic acid.   6. 5- (4-Hydroxyethylcarbamoylphenylazo) -salicylic acid and the sodium salt thereof,   7. 5- (α-Methylcarboxymethylcarbamoyl-4-phenylazo) -acid salicylic.   8. 5 - [(4-carboxymethylphenyl) -sulfamoyl-4-phenylazo] - salicylic.   9. 5- (Carboxypentylcarbamoyl-4-phenylazo) -salicylic acid.   10. 5- (α-Dimethylaminocarboxypentylcarbamoyl-4-phenyl) acid   azo) -salicylic acid and the sodium salt thereof.   11. 5- (Diethylaminoethylcarbamoyl-4-phenylazo) -salicylic acid   lic. 12. Pharmaceutical composition containing at least one compound of general formula COOH R-NH-X X 3 N = N ^ O OH   wherein X is -SQ2- or -CO-, and R is either an unsubstituted or substituted non-heterocyclic aromatic ring, or a radical of the general formula - (CH2) nY, wherein Y is   is either a hydroxyl group or a substituted amino group   titué or non-substituted, or a carboxylic acid or sulfonic acid group, and n is an integer selected from 1 to 6, and wherein one or more hydrogen atoms of the radical   alkene may be replaced by substituted amino groups   killed or unsubstituted, or by alkyl radicals, and in the   the radical - (CH2) nY is attached to the nitrogen atom either directly or via a benzene ring, and / or containing at least one ester of this compound and / or at least one salt a pharmaceutically acceptable toxicant of this compound, in admixture with a solid pharmaceutical diluent or carrier or liquid.   13. Process for the preparation of compounds according to the general formula given in claim 12, and salts thereof, wherein an amine of the general formula R NH-XO NH 2 (II)   wherein X is -SO2- or -CO- and R is either an unsubstituted or substituted non-heterocyclic aromatic ring or a radical of the general formula - (CH2) n-Y, wherein Y   is either a hydroxyl group or a substituted amino group   titué or non-substituted, a carboxylic acid or sulfonic acid group, and n is an integer selected from 1 to 6, and   in which one or more hydrogen atoms of the alkenic radical   can not be replaced by substituted or unsubstituted amino groups, or by alkyl radicals, and in which the radical (CH2) nY is attached to the nitrogen atom either directly or via a benzene ring, is diazotized and associated with salicylic acid, after which, if   the compound obtained is salified with an organic base. that or inorganic non-toxic. 24933 1 2   14. Compounds according to the general formula given to the   cation 12, prepared according to the method described in claim 13. BIOREX LABORATORIES LTD. By Proxy Cabinet SCOPI